BIOSYNTHESIS OF NOVEL ADRENOCORTICAL STEROIDS

新型肾上腺皮质类固醇的生物合成

• 批准号: 2856835
• 负责人: JOHN M HAMLYN
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856835
• 关键词: adrenal glands; aldosterone; animal tissue; chemical structure function; gas chromatography; immunologic assay /test; mass spectrometry; nuclear magnetic resonance spectroscopy; ouabain; radioimmunoassay; radiotracer; sodium potassium exchanging ATPase; steroid biosynthesis; tissue /cell culture

DESCRIPTION (Adapted from applicant's abstract): Cardiac glycosides are steroidal compounds of plant origin that enjoy widespread use in medicine and the basic sciences. They bind with high affinity and specificity to a highly conserved site on the sodium-potassium pump. Overwhelming structural and functional evidence shows the presence of an isomer of ouabain in the circulation, and tissues of mammals including man and cattle. Much evidence suggests that the adrenal cortex may be the primary source of the circulating isomer (i.e., an "adrenal derived endogenous ouabain, AEO). However, the biosynthesis of AEO by mammals has not been described. The successful outcome of this investigation may constitute a major advance in steroid biochemistry and lend further credence to the evidence that AEO and related steroids are of physiological and medical significance. The proposal describes experiments using established procedures that investigate the synthesis of AEO by bovine adrenocortical tissue and cells in culture. The aims are: 1) to determine whether common steroidogenic precursors support synthesis and adrenal secretion of AEO and aldosterone; 2) to use radiolabeled precursors to determine whether they can be transformed by an ordered sequential process to AEO, and the point at which the pathway diverges from that for aldosterone; 3) to determine the functional activity of the secreted materials by analysis of the binding and inhibitory mechanism of action on the sodium pump, and 4) to investigate the structure of the secreted AEO and stable biologically active precursors using mass spectral and nuclear magnetic resonance techniques. Detailed knowledge of the structure of the adrenal materials can provide new insights into the design of improved cardiotonics as well as novel agents that interfere with receptor binding and adrenal biosynthesis.

描述（改编自申请人的摘要）：心脏糖苷为 植物起源的类固醇化合物，可在医学中广泛使用 和基本科学。 它们具有高亲和力和特异性的结合 高度保守的位置在钠钾泵上。 压倒性的结构 功能证据表明，乌巴因的异构体在 循环以及包括人和牛在内的哺乳动物的组织。 很多证据 表明肾上腺皮质可能是 循环异构体（即，“肾上腺衍生的内源性ouabain，aeo）。 但是，尚未描述哺乳动物对AEO的生物合成。 这项调查的成功结果可能构成重大进步 在类固醇生物化学中，并进一步证明了AEO的证据 相关的类固醇具有生理和医学意义。 这 提案描述了使用既定程序来描述实验 牛在培养中由牛肾上腺皮质组织和细胞合成AEO。 目的是：1）确定是否常见的类固醇生成前体 支持AEO和醛固酮的合成和肾上腺分泌； 2）使用 放射标记的前体，以确定是否可以通过 对AEO的有序顺序过程，以及路径的点 与醛固酮不同； 3）确定功能活动 通过分析结合和抑制性的分泌材料 钠泵上的作用机理，4）研究结构 使用质量的分泌的AEO和稳定的生物活性前体 光谱和核磁共振技术。 详细的知识 肾上腺材料的结构可以为 改进的心元学以及干扰的新型代理商的设计 受体结合和肾上腺生物合成。